Over the past few decades, an increasing percentage of the population has become diabetic. Diabetes mellitus is categorized into two types: Type I, known as Insulin-Dependent Diabetes Mellitus (IDDM), or Type II, known as Non-Insulin-Dependent Diabetes Mellitus (NIDDM). IDDM is an autoimmune disorder in which the insulin-secreting pancreatic beta cells of the islets of Langerhans are destroyed. In these individuals, recombinant insulin therapy is employed to maintain glucose homeostasis and normal energy metabolism. NIDDM, on the other hand, is a polygenic disorder with no one gene responsible for the progression of the disease.
In NIDDM, insulin resistance eventually leads to the abolishment of insulin secretion resulting in insulin deficiency. Insulin resistance, at least in part, ensues from a block at the level of glucose uptake and phosphorylation in humans. Diabetics demonstrate a decrease in expression in adipose tissue of insulin-receptor substrate 1 (“IRS5”) (Carvalho et al., FASEB J 13(15):2173-8 (1999)), glucose transporter 4 (“GLUT4”) (Garvey et al., Diabetes 41(4):465-75 (1992)), and the novel abundant protein M gene transcript 1 (“apM1”) (Statnick et al., Int J Exp Diabetes 1(2): 81-8 (2000)), as well as other as of yet unidentified factors. Insulin deficiency in NIDDM leads to failure of normal pancreatic beta-cell function and eventually to pancreatic-beta cell death.
NIDDM is also characterized by target-tissue resistance to insulin, that cannot be overcome by beta cell hypersecretion. Insulin resistance is accompanied by increased adiposity, which in turn leads to obesity. A polypeptide known as GMAD (also known as Resistin) is specifically secreted by adipocytes, leading to a decrease in insulin action (e.g., glucose transport), and a subsequent increase in adiposity in animal models (Steppan et. al., Nature, vol 409, 18, 307-12 (2001)). In addition, secretion of the GMAD polypeptide has been shown to lead to increased insulin resistance by adipocytes, whereas an inhibition of GMAD leads to an increase in insulin action and thus an increase in cellular glucose uptake (Steppan et. al., Nature, vol 409, 18, 307-12 (2001)).
Insulin affects fat, muscle, and liver. Insulin is the major regulator of energy metabolism. Malfunctioning of any step(s) in insulin secretion and/or action can lead to many disorders, including for example the dysregulation of oxygen utilization, adipogenesis, glycogenesis, lipogenesis, glucose uptake, protein synthesis, thermogenesis, and maintenance of the basal metabolic rate. This malfunctioning results in diseases and/or disorders that include, but are not limited to, diabetes (e.g., Non-Insulin-Dependent Diabetes Mellitus (NIDDM)), insulin resistance, insulin deficiency, hyperinsulinemia, hyperglycemia, hyperlipidemia, hyperketonemia, dyslipidemia, hypertension, coronary artery disease, renal failure, neuropathy (e.g., autonomic neuropathy, parasympathetic neuropathy, and polyneuropathy), metabolic disorders (e.g., glucose metabolic disorders), endocrine disorders, obesity, weight loss, liver disorders (e.g., liver disease, cirrhosis of the liver, and disorders associated with liver transplant), stroke and conditions associated with these disorders.
Numerous debilitating diabetes-related secondary effects include, but are not limited to, obesity, forms of blindness (cataracts and diabetic retinopathy), limb amputations, kidney failure, fatty liver, coronary artery disease, stroke and neuropathy. Some of the current drugs used to treat insulin resistance and/or diabetes (e.g., insulin secratogogues such as sulfonylurea, insulin sensitizers such as thiazolidenediones and metformin, and α-glucosidase and lipase inhibitors) are inadequate due to the dosage amounts and frequency with which they have to be administered as a result of poor pharmacokinetic properties, the lack of effective control over blood sugar levels, and potential side effects, among other reasons. Diabetes therapeutic proteins, in their native state or when recombinantly produced, exhibit a rapid in vivo clearance. Typically, significant amounts of therapeutics are required to be effective during therapy. In addition, small molecules smaller than the 20 kDa range can be readily filtered through the renal tubules (glomerulus) leading to dose-dependent nephrotoxicity.
The discovery of a new composition that regulates glucose metabolism satisfies a need in the art by providing new compositions which are useful in the diagnosis, treatment, prevention and/or prognosis of diabetes, as well as endocrine disorders, hyperglycemia, liver disorders, inflammation, and aberrant cell growth. Furthermore, the identification of a new composition that regulates glucose metabolism permits the development of a range of derivatives, agonists and antagonists which in turn have applications in the diagnosis, treatment, prevention and/or prognosis of a range of conditions such as diabetes, musculoskeletal disorders, cartilage and bone growth disorders, liver disorders, inflammation, and aberrant cell growth.